Yarrow supercritical extract exerts antitumoral properties by targeting lipid metabolism in pancreatic cancer

RESEARCH ARTICLE Yarrow supercritical extract exerts antitumoral properties by targeting lipid metabolism in pancreatic cancer Lamia Mouhid1☯, Marta Gómez de Cedrón ID1☯*, Elena Garcı́a-Carrascosa1, Guillermo Reglero1,2, Tiziana Fornari2, Ana Ramı́rez de Molina ID1* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Molecular Oncology and Nutritional Genomics of Cancer, IMDEA-Food Institute, CEI UAM + CSIC, Madrid, Spain, 2 Production and Characterization of Novel Foods Department, Institute of Food Science Research CIAL, CEI UAM + CSIC, Madrid, Spain ☯ These authors contributed equally to this work. * (ARDM); (MGDC) Abstract OPEN ACCESS Citation: Mouhid L, Gómez de Cedrón M, Garcı́aCarrascosa E, Reglero G, Fornari T, Ramı́rez de Molina A (2019) Yarrow supercritical extract exerts antitumoral properties by targeting lipid metabolism in pancreatic cancer. PLoS ONE 14(3): e0214294. https://doi.org/10.1371/journal. pone.0214294 Editor: Olga A. Sukocheva, Flinders University of South Australia, AUSTRALIA Received: September 27, 2018 Accepted: March 11, 2019 Metabolic reprogramming is considered a hallmark of cancer. Currently, the altered lipid metabolism in cancer is a topic of interest due to the prominent role of lipids regulating the progression of various types of tumors. Lipids and lipid-derived molecules have been shown to activate growth regulatory pathways and to promote malignancy in pancreatic cancer. In a previous work, we have described the antitumoral properties of Yarrow (Achillea Millefolium) CO2 supercritical extract (Yarrow SFE) in pancreatic cancer. Herein, we aim to investigate the underlaying molecular mechanisms by which Yarrow SFE induces cytotoxicity in pancreatic cancer cells. Yarrow SFE downregulates SREBF1 and downstream molecular targets of this transcription factor, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). Importantly, we demonstrate the in vivo effect of Yarrow SFE diminishing the tumor growth in a xenograft mouse model of pancreatic cancer. Our data suggest that Yarrow SFE can be proposed as a complementary adjuvant or nutritional supplement in pancreatic cancer therapy. Published: March 26, 2019 Copyright: © 2019 Mouhid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. Funding: This work was supported by Ministerio de Economı́a y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL201348943-C2 and AGL2016-76736-C3), Gobierno regional de la Comunidad de Madrid (P2013/ABI2728, ALIBIRD-CM) and EU Structural Funds. The funders had no role in study design, data collection Introduction Pancreatic cancer is the second leading cause of cancer-related deaths worldwide. It is an aggressive malignancy with poor prognosis: the overall 5-year survival rate is less than 5%. Risk factors described to be linked with its development are obesity and chronic pancreatitis, but also tobacco smoking, heavy alcohol intake, unbalanced diets, or high red meat intake [1,2]. Given the absence of indicators of illness, it is often diagnosed at metastatic late stages. Although surgery remains the main beneficial treatment followed by chemotherapy and radiation, current therapies do not improve patient’s survival. Therefore, the development of effective therapeutic strategies targeting molecular alterations associated with pancreatic tumor growth and the resistance to apoptosis are needed to improve their survival. PLOS ONE | https://doi.org/10.1371/journal.pone.0214294 March 26, 2019 1 / 21 Yarrow extract as a supplement in pancreatic cancer and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: SFE, Supercritical Fluid Extraction; SREBF, Sterol Regulatory Element Binding Transcription Factor; FASN, Fatty Acid Synthase; SCD, Stearoyl-CoA Desaturase; 5-fu, 5-fluororacil. In the last years, there has been a growing interest in the use of phytochemicals and dietaryderived compounds for prevention or for cancer treatment [3,4]. Thus, some of them have shown antitumoral properties in vitro and in vivo [4–6]. In this regard, there are some phytochemicals derived from natural sources, such as taxol and camptothecin, which are extensively used in clinics to treat several tumors [7,8]. Nevertheless, pancreatic cancer remains one of the most resistant tumor [9]. Current chemotherapy is based on the use of gemcitabine, 5-fluorouracil, irinotecan and/or oxaliplatin but new complementary approaches are required. On the other hand, metabolic reprogramming is well-recognized as a hallmark of cancer [10] and thus, there is an increased interest for targeting its altered metabolism. Tumors display high rates of cell proliferation and they can acquire malignancy associated to stemness and invasive properties. Moreover, highly proliferative cells hold an exacerbated glucose uptake sustaining aerobic glycolysis (Warburg effect) for anabolic processes [11–13]. In addition, increased glutamine uptake and glutaminolysis support carbon and nitrogen backbones for anabolic purposes. Nitrogen, in addition to its role in protein and nucleotide biosynthesis, is crucial for the synthesis of glutathione and essential to maintain the redox homeostasis [12–14]. Cancer cells are also characterized by having an increased de novo fatty acid synthesis which contributes to the carcinogenic process and cancer cell survival. Metabolic fatty acid (FA) enzymes are essential for neoplastic growth as well as for the signaling of key tumorigenic pathways. During tumor development, lipid associated alterations include an increase in lipogenic enzymes expression such as fatty acid synthase (FASN), acetyl carboxylase (ACC), stearoyl-CoA desaturase (SCD), ATP citrate lyase (ACLY), and an increase in the synthesis and uptake of cholesterol. As a result, tumor cells can control membrane fluidity, which has an impact on intracellular oncogenic signaling pathways, and sharpens resistance to chemotherapeutics. In addition, the increased storage of lipid and cholesterol molecules into lipid droplets allows tumor cells to gain independence from the extracellular nutrient availability [15,16]. In this context, many authors have described alterations in expression of lipid metabolic genes, and their link with the development and prognosis in cancer [17,18]. Thus, targeting specific enzymes involved in fatty acid and cholesterol synthesis, or affecting genes involved in their transcriptional regulation could be a novel approach for cancer treatment [19,20]. Recently we have described the antitumoral properties of Achillea Millefolium derived ext (...truncated)